Osteoarthritis and rheumatoid arthritis are characterized by progressive destruction of articular cartilage. Nondestructive techniques for accurately assessing the structural and functional integrity of cartilage, such as magnetic resonance imaging (MRI), are essential for defining the natural history of these joint diseases and for evaluating the effects of preventive and therapeutic interventions. Our long-term goal is to establish MRI techniques for evaluating the compositional and functional integrity of articular cartilage, effectively establishing nondestructive surrogates to currently utilized biochemical and histologic techniques. Based on our progress during the first two cycles of this award and on work by other groups, we have recently turned our focus to three parameters which have demonstrated the most practical and molecular-specific MR measurements: delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC), T2, and diffusion, dGEMRIC has demonstrated sensitivity and specificity to GAG;T2 imaging of cartilage is based on the sensitivity of T2 to hydration, collagen molecular structure, and collagen architectural organization through the magic angle effect;diffusion has been shown to demonstrate the restriction of water in cartilage by the collagen matrix, and has the potential to demonstrate the collagen fibril orientation. In this coming cycle, we propose to further develop the multiparametric approach to yield improved specificity for aspects of the collagen component, as well as improving the potential of clinical applications. The specific aims are: (1) Further develop diffusion imaging as a metric of collagen orientational structure using excised bovine and human cartilage/bone samples, (2) enable T2 and diffusion imaging in the presence of GdDTPA (for dGEMRIC studies) by comparing the measurements with and without GdDTPA, (3) address the limiting factors in clinical dGEMRIC imaging by developing three dimensional and 3T imaging, and (4) initiate clinical studies of dGEMRIC and T2 in two clinical situations of early osteoarthritis and patients post ACL injury. Our overall research goal has remained the same: developing NMR/MRI techniques to measure the compositional and functional properties of cartilage. In this cycle we plan to continue towards our goal by focusing in on the parameters that show the most promise for specific and sensitive information regarding cartilage health, disease, and repair, and furthering the application to clinical studies.